The linear ubiquitin chain assembly complex (LUBAC) includes three protein subunits: HOIP (also known as RNF31), HOIL-1L (also known as RBCK1), and SHARPIN. Niu et al., EMBO J., 30:3741-3753 (2011). LUBAC catalyzes the formation of head-to-tail linear ubiquitin polymers and has been linked to the activation of canonical nuclear factor kappa B (NF-κB) signaling. Tokunaga et al., Nature Cell Biol., 11: 123-132 (2009). Other ubiquitin chains, e.g., K63 linked chains, have been shown to regulate NF-κB activation in response to certain stimuli, including antigen stimulation of lymphocytes and TNF-α therapy. LUBAC and K63 ubiquitin chains appear to function differently and have different roles in NF-κB signaling. Iwai et al., EMBO Reports, 10: 706-713 (2009) (“Iwai et al.”).
NF-κB refers to a family of homo and heterodimer transcription factors that integrate and coordinate signals from infectious and inflammatory agents and generate specific responses in a variety of cell types. Hymowitz et al., Nature Reviews Cancer, 10: 332-340 (2010). In their inactive resting state, NF-κB proteins are bound by inhibitory proteins (“IκBs”) that sequester NF-κB in the cytoplasm and prevent its translocation to nucleus. The canonical NF-κB pathway is activated in response to specific stimuli (e.g., pro-inflammatory cytokines or infectious agents) and involves the activation of IκB kinase (“IKK”) which is composed of several subunits, including a mater regulatory subunit referred to as NF-κB essential modulator (NEMO). IKK phosphorylates IκBs leading to the degradation of IκBs and release of NF-κB for translocation to the nucleus where NF-κB induces expression of stimulus-specific genes. See, e.g., Iwai et al. (2009).
Many diseases, including cancer, involve dysregulated NF-κB signaling. Given the complexity of signaling pathways that converge on NF-κB, there is a desire to understand how NF-κB activity is dysregulated in these disease states. There is also a desire to develop therapeutic agents which are useful in the treatment of NF-κB dysregulated diseases.